15 NEW THERAPIES 'MADE IN CATALONIA' - October 2019 - Biocat

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15 NEW THERAPIES
‘MADE IN
CATALONIA’
October 2019
The biomedical start-ups in the BioRegion of Catalonia currently have almost 20
therapies in the clinical phase. Some of these therapies may reach patients by 2025.
What might the next made-in-Catalonia drugs be?

A new company is launched every week in the BioRegion of Catalonia, the Catalan life
sciences and health sector. Since 2008, investment in these start-ups has multiplied by 12,
and the number of foreign investors in these emerging companies has risen from 0 to more
than 50 in 10 years.

What are these resources used for? Bringing a new drug to market takes more than 10 years
and costs more than €1 billion, and only 1 out of every 10,000 potential drugs ends up reaching
patients. Currently, Catalan biomedical start-ups have almost 20 therapies in the clinical
phase, a significant increase over the 7 that were in the pipeline in 2013. As a result of the
sector’s development, Biocat estimates that some of these drugs may actually reach patients
by around 2025. Let’s review these potential drugs in the most advanced phases which are
currently being developed in the BioRegion of Catalonia:

1. Vaccines and infectious diseases
The Catalan HIV vaccine from AELIX Therapeutics

A vaccine that allows people infected with HIV to keep the virus under control by
re-educating their own immune system: this is the goal of AELIX Therapeutics with
its therapeutic vaccine based on the immunogen HTI. AELIX is a spin-off of the
HIVACAT program led by IrsiCaixa and the Hospital Clínic with the support of partners like
“la Caixa” and Esteve.

HTI is an immunogen which was developed based on observations of the immune responses
of individuals who were able to control HIV themselves. It is injected into the organism via
vectors. This sequence would allow individuals who cannot control the virus themselves to
develop an immune response equivalent to the response of those who can spontaneously
control the virus.

In 2016, AELIX closed the first round of funding with €11.5 million. In 2017, the
company, which is headquartered in the Barcelona Science Park, started its first
phase Ib / IIa clinical trial, called AELIX-002, in which 45 individuals infected by
HIV took part. This study is being conducted at the Hospital Germans Trias i Pujol,
and the final results will be available in late 2020.

In October 2018, AELIX embarked on a partnership with Gilead Sciences to conduct another
phase II study, called AELIX-003. In this study, the HTI vaccine is administered along with
the Gilead drug vesatolimod, a combination which is expected to lead to the elimination of
the cells infected with the virus. The results of this study are expected to be available in late
2021.

So far, AELIX has raised €13 million to finance the development of HTI. The scenario
envisioned by the company is to license the therapy to a pharmaceutical company and sign
further partnership agreements.

       Biocat – 15 new therapies made in Catalonia                                                  2
RUTI, the tuberculosis vaccine from Archivel Farma

Currently, there are around 15 potential vaccines against tuberculosis in the clinical phase
around the world, the majority of which aim to prevent the disease. One of the few therapeutic
vaccines to treat it is being developed in Catalonia, more specifically in Badalona: it is called
RUTI and it is being developed by Archivel Farma.

Archivel Farma was founded in 2005 to develop the RUTI vaccine discovered by Dr Pere-Joan
Cardona from the Institut de Recerca Germans Trias i Pujol (IGTP) with the financing of
Archivel Technologies. In its different developmental stages, the company has raised more
than €20 million from private investors, family offices, venture capital funds and domestic and
European public funds. Currently, its main investors are the Teodoro García Trabadelo Group
and Archivel Technologies, and Laboratoris Reig Jofré is a minority shareholder.

Archivel Farma is focusing its strategy on developing RUTI to treat multi-drug-resistant
tuberculosis. The vaccine is being tested in a phase II clinical trial with 27 patients in a total
of four hospitals in Groningen (Netherlands) and Ukraine. The results are expected to be
available in late 2020.

With assistance from the European H2020 program, and within the consortium known as
STRITUVAD, another phase II clinical trial will soon get underway to test the RUTI vaccine in
two groups of patients in India: one with active tuberculosis and the other with multi-drug-
resistant tuberculosis. In the trial, a total of 140 patients will be recruited in two different
hospitals, one of them the renowned AIIMS (All India Institute of Medical Science) in New
Delhi.

The vaccine’s capacity to activate a broad response in the immune system against different
antigens has driven Archivel Farma to study its use for other conditions as well, such as to
treat rhinitis and other allergic diseases, and immunotherapy for bladder cancer, an
indication in which a phase I clinical trial is already underway at the Hospital Germans Trias i
Pujol. This trial has 40 patients, and the results are expected in mid-2020.

Archivel Farma has its own production plant where the RUTI vaccine is manufactured in a
GMP environment. RUTI was designated an orphan drug by the European Medicines Agency
in 2017.

2. Oncology
Autophagia, the promise of AbilityPharma in oncology

Ability Pharmaceuticals’ proposal for oncology is ABTL0812, a compound administered orally
which causes the death of tumor cells by autophagia (self-digestion). In phase I/Ib, which
involves 29 patients with solid advanced tumors, ABTL0812 showed a high degree of safety
and tolerability, and signs of efficacy were observed.

AbilityPharma has just closed a round of €3.5 million to complete phase II clinical studies in
Europe in patients with endometrial cancer or squamous-cell lung cancer, as a first-line
treatment in combination with chemotherapy, and as a chronic maintenance treatment after
various cycles of chemotherapy. The study is being conducted in leading oncological hospitals
in Spain and France (including ISO and Vall d’Hebron). In the United States, the FDA has
       Biocat – 15 new therapies made in Catalonia                                                   3
already approved this same study (December 2017) and the protocol of another phase II study
in pancreatic cancer (January 2018). This study will be financed with international public
funding. ABTL0812 was approved for an Orphan Drug Designation (ODD) for pancreatic
cancer, bile duct cancer and pediatric neuroblastoma cancer by the FDA in the United
States and the EMA in Europe.

Ever since it was founded in 2011 after splitting off from AB-Biotics, Ability Pharmaceuticals
has raised more than €15 million, and its current shareholders include the venture capital funds
Fitalent (from the Everis Group) and Sodena, along with its founders, private investors and
public aid and loans. The company has just taken a step forward by appointing Maribel Berges
General Manager after promoting to Carles Domènech Executive President and Scientific
Director.

Located in the Vallès Technology Park and the UAB Research Park, in 2016 AbilityPharma
signed an agreement with SciClone Pharmaceuticals to develop and commercialize the
product in China, and it hopes to reach a licensing agreement with a global pharmaceutical
company in order to continue to develop the drug and commercialize it in the future.

Hospital Clínic’s own CAR-T therapy

Three years ago, just like some university hospitals in the United States and China, the
Hospital Clínic of Barcelona started preparing for its own academic CAR-T therapy so it does
not depend on a pharmaceutical company to supply it at high prices and with the restrictions
associated with a commercial product. It was christened the ARI Project in honor of the patient
Ari Benedé, who with his family spearheaded a campaign to secure financing.

So far, the Hospital Clínic has treated the 35 patients required by the Spanish Medicines
Agency (AEMPS) for its CAR-T therapy (called ARI1) to be used as a free treatment in patients
with lymphoma and acute lymphoblastic leukemia in the National Health System. The
Hospital Clínic expects it to be authorized in late 2019, and once approved, it can benefit a
large number of patients at Spanish hospitals. Unlike the CAR-T therapies of other
pharmaceutical companies, the CAR-T therapy cells at the Hospital Clínic may not be sent to
other countries. According to the Hospital Clínic, the cost of the therapy to the public system
will be approximately one-third of the cost of pharmaceutical drugs.

The Hospital Clínic’s CAR-T therapy, which is a bit different from the one developed by
Novartis, is being tested for acute lymphoblastic leukemia and lymphoma in adults, as well
as in acute lymphoblastic leukemia in children (Hospital Sant Joan de Déu). The Hospital
Clínic also plans to start a clinical study with myeloma patients with another CAR-T therapy
called ARI2 in November 2019.

VCN Biosciences: Viruses that attack tumors

Designing new treatments for cancer using oncolytic adenoviruses is the goal of VCN
Biosciences, a company founded in 2009 by three researchers from the Institut Català
d’Oncologia (ICO) and the Institut d’Investigació Biomèdica de Bellvitge (IDIBELL). In 2012,
40% of its capital was acquired by Grifols, which now houses the company within its corporate
facilities in Sant Cugat del Vallès. The company is currently raising a new round of funding and
       Biocat – 15 new therapies made in Catalonia                                                 4
forging partnerships with pharma companies working in the field of immune checkpoint
inhibitors which have already proven their products’ ability to modulate their therapeutic
activity.

VCN Biosciences’ most advanced candidate is VCN-01, an adenovirus which is selectively
replicated in tumor cells and which acts to deteriorate the hyaluronic acid in the matrix around
the tumor by expressing the human hyaluronidase enzyme. The degradation of this matrix
provides the virus with access to the tumors and facilitates the effects of chemotherapy,
therapeutic antibodies and the immune system, which is stimulated from the effect of the
selective intratumoral replication of the virus.

VCN-01 is currently in the clinical development phase with patients who have different kinds
of tumors (pancreatic cancer, retinoblastoma, head and neck tumors). The initial studies
confirmed the safety of the therapy and the therapeutic mechanisms of the product, while also
providing the first evidence of patients’ longer survival time compared to standard treatments.

The company is currently evaluating the combination of VCN-01 with immune checkpoint
inhibitors: it has already started a first clinical trial in patients with metastatic squamous cell
carcinoma of the head and neck for whom treatment with this kind of agent had previously
failed, and it plans to start more. The hope is that these studies will prove VCN-01’s ability to
immunologically stimulate tumors and to sensitize the immune checkpoint inhibitors.

VCN Biosciences is also developing a second candidate (VCN-11), which not only expresses
hyaluronidase but is also capable of avoiding the neutralizing antibodies generated against the
adenovirus. Additionally, the product has an even more optimal toxicity profile. These
properties pave the way for the clinical use of VCN-11 in repeated administration plans. The
product is currently in the preclinical phase, and clinical trials are expected to get underway in
2021.

ORY-1001, epigenetics of Oryzon in oncology

With a research center in Cornellà de Llobregat (Barcelona), Oryzon is the longest-standing
biotech company in the BioRegion of Catalonia. The company led by Carlos Buesa develops
new epigenetic therapies to treat oncological and neurodegenerative diseases using the
enzyme LSD1 as the therapeutic target.

Oryzon has quoted on the Spanish stock market since December 2015. In 2015-2016, the
company raised €32 million, with additional capital increases in 2017 (€18.2M), 2018 (€13M)
and 2019 (€20M), in which the company added specialized investors from the United States
and Europe.

The Oryzon pipeline currently includes three compounds, two of them in the clinical phase:
iadademstat (also known as ORY-1001), an LSD1-selective inhibitor for cancer, and
vafidemstat (also known as ORY-2001), an LSD1-optimised inhibitor for CNS for neurological
diseases.

Oryzon’s business model consists in developing its molecules up to phase II and then engaging
in partnerships for the subsequent clinical development and commercialization phases.

       Biocat – 15 new therapies made in Catalonia                                                    5
Thus, from 2014 to 2017, Oryzon was in a partnership with Roche, which led to revenues of
more than 23 million dollars to develop iadademstat (ORY-1001), a small, orally administered
molecule with a powerful differentiating effect in hematological and solid cancers, like small-
cell lung cancer. Oryzon regained the rights to the drug and has made headway towards
developing it with two phase II clinical studies underway: ALICE, to evaluate the safety and
tolerability and determine the dose and efficacy of iadademstat in combination with standard
treatment with azacytidine in patients recently diagnosed with acute myeloid leukemia
who are not eligible for intensive chemotherapy; and CLEPSIDRA, to evaluate the safety
and tolerability and determine the dose and efficacy of iadademstat in combination with
platinum-etoposide in patients with small-cell lung cancer. Just a few days ago, the company
presented positive results on the efficacy of this latter study as part of the ESMO-2019
international conference in Barcelona. The final results of these studies are expected in the
second half of 2020.

3. Neurology
The epigenetic candidate from Oryzon in neurology: ORY-2001

The Oryzon pipeline (see Oncology section above) currently includes an LSD1-optimised
inhibitor for CNS for neurological diseases: vafidemstat (also known as ORY-2001).

Vafidemstat (ORY-2001) is a small, orally-administered molecule which acts on different levels
to lower cognitive deterioration, memory loss and neuroinflammation, in addition to having
neuroprotective effects. Oryzon has several phase II clinical studies underway with this
molecule: the REIMAGINE and REIMAGINE-AD studies on aggressiveness in psychiatrically
ill patients (autism spectrum syndrome, borderline personality disorder, attention deficit
and hyperactivity disorder in adults) and Alzheimer’s patients, respectively; the ETHERAL
and ETHERAL-US studies in patients with Alzheimer’s; and the SATEEN study on multiple
sclerosis. The company plans to release the results of these studies starting in November
2019 and throughout 2020.

Bionure’s commitment to multiple sclerosis

An optimal candidate to treat neurodegenerative diseases like multiple sclerosis: this is
Bionure’s goal with its first drug: BN201. After proving it can protect neurons and promote
remyelination in model animals, the molecule has completed a phase 1 trial in the United
Kingdom in 48 healthy volunteers. Bionure hopes to launch phase 2 trials in early 2020 to
prove the efficacy of BN201 in patients who suffers from acute episodes of optic neuritis.

The company is currently focusing its efforts on multiple sclerosis and acute optic neuritis, a
rare ophthalmologic disease for which BN201 is designated an orphan drug in Europe and the
United States.

A spin-off of IDIBAPS and the CSIC, Bionure was founded in 2009 and is based at the
Barcelona Science Park. Late 2017, the company welcome a first institutional VC investor, Alta
Life Science, which led a Series A round to finance a first clinical phase 1 study and recently
closed an internal round and a second crowdfunding round to fund regulatory and technical
preparations for the next phase 2 study. To date the company has raised a total of €12 millions.
       Biocat – 15 new therapies made in Catalonia                                                 6
Bionure strengthened his executive team by recruiting Dr Laurent Nguyen as CEO in
September 2018 and Dr Lucia Septien as CMO in May 2019. The company intends to run the
next proof-of-concept phase 2 study in patients and thereafter consider various partnering, exit
or refinancing options.

4. Rare diseases
Minoryx: 50 million to combat rare diseases

“Finding innovative therapies for patients with rare diseases”: this is the personal commitment
with which Marc Martinell, founder and CEO of Minoryx, launched one of the biotech
companies with the most meteoric rise in the BioRegion of Catalonia. With its TecnoCampus
in Mataró (Barcelona), the company has opened a branch in Belgium after closing one of the
largest investment rounds in the sector: €21.3 million, led by the Belgian Fund+ in 2018. Since
it was created, Minoryx has raised €50 million.

Its drug MIN-102 (leriglitazona) is currently in a phase II/III clinical trial to treat
adrenomyeloneuropathy (AMN), the most common phenotype of X-linked
adrenoleukodystrophy (X-ALD), a disease that affects one out of every 17,000 children born
in the world. AMN is characterised by gradual neurodegeneration which affects motor function
after the age of 20, and there is no pharmacological treatment for it. Minoryx’s drug is the most
advanced drug to treat this disease currently in clinical development, and it has been
categorized as an orphan drug to treat X-ALD in both Europe and the United States. Treatment
lasts around 2 years, and currently the majority of patients in the clinical study have already
passed the one-year mark. The results of the study are expected in late 2020.

Minoryx is also ready to launch a second study with MIN-102 in X-ALD. This is a phase II study
to treat cerebral X-ALD (CALD) in pediatric patients. This phenotype is the most aggressive
one; it typically affects children under the age of 10 and is characterized by a severe
inflammation of the brain that leads to death within 2-4 years. Currently, the only therapeutic
option is a bone marrow transplant.

MIN-102 is also in phase II to treat Friedreich’s ataxia (FRDA), a rare genetic disease which
affects one out of every 40,000 people in the world and is characterized by a loss of
coordination and muscle strength which ultimately leads to death. Precisely this October,
Minoryx has finished recruiting 39 patients in Europe for this study, called FRAMES, whose
goal is to evaluate the effect of MIN-102 on the progression of the disease. Results are
expected at the end of 2020.

SOM Biotech: Accelerating cures for rare diseases

SOM Biotech, headquartered in the Barcelona Science Park, is specialized in discovering and
developing drugs to treat rare diseases. Ever since it was founded in 2009, SOM Biotech has
raised more than €12 million from private capital and public subsidies and loans. Fifty-nine
percent of its shareholders are international, 26% of them from outside Europe.

SOM Biotech closed a round of €7 million in March 2019 in order to finish the phase IIa study
of an innovative treatment for chorea associated with Huntington’s disease: the SOM3355
       Biocat – 15 new therapies made in Catalonia                                                  7
compound. This is a drug which is currently sold for high blood pressure in Asian markets. The
drug’s new activity was discovered by SOM Biotech via its computational platform based on
artificial intelligence algorithms. The company expects this drug to reach the market within five
years, with annual estimated sales surpassing €600 million.

With regard to the company’s licensing agreements, in 2016 SOM Biotech signed an exclusive
global licensing agreement with the US company Corino Therapeutics Inc. for the clinical
development and sale of the drug SOM0226 to treat amyloid transthyretin amyloidosis
(ATTR), a rare disease which affects 50,000 people in the world. The operation closed after a
therapeutic agent discovered by the company yielded very promising results in the phase IIa
clinical study. In 2018 as well, SOM Biotech signed an exclusive global licensing agreement
with U-Cell Therapeutics Inc. (Singapore) for the SOM0777 compound to treat brain cancer.

SOM Biotech has an extensive product portfolio which includes projects about to enter phase
IIa (SOM1201, Adrenoleukodystrophy), other compounds ready to start animal studies
(SOM0208, Niemann Pick C and SOM1311, Phenylketonuria), and yet others in the in-vitro
stage (Duchenne Muscular Dystrophy, Gaucher Disease, Fabry Disease, etc.). The
company has also reached several partnership agreements with companies in the sector
providing them support to develop the drugs in their portfolios.

5. Cardiovascular and blood
The vasculoprotective drug against stroke from FreeOx Biotech

Stroke, one of the leading causes of death and disability around the world, is the main target
of FreeOx Biotech, a young biotech company founded in 2017 by five entrepreneurs from
Barcelona and Pittsburgh as a spin-out of Hospital Clínic de Barcelona-IDIBAPS.

The company has two molecules to treat stroke and other diseases of the central nervous
system: Ox-01 and Ox-02. The more advanced one, Ox-01, is based on uric acid and has a
proven preventative effect against the damage caused by the reperfusion after stroke. Ox-
01 has concluded its phase IIb clinical trial with 421 patients in 10 benchmark hospitals in
Spain, showing statistically significant clinical effectiveness as a vasculoprotective drug in
strokes. Specifically, subgroups of patients previously identified as highly responsive, namely
women, hyperglycemic patients and patients subjected to mechanical thrombectomy, showed
outstanding results in terms of efficacy and safety.

In November 2018, the company concluded its first round of €500,000 with private investors in
order to prepare to embark on clinical phase III of Ox-01 in 2020 and conduct pre-clinical
studies with Ox-02. The company is seeking investors and/or licensees for a Series B round
to complete the clinical development of Ox-01 and secure its commercial authorization in the
leading global markets.

The antihemorrhagic agent in phase III from Thrombotargets

Even though the company got its start in 2005 by offering molecule library screening to
pharmaceutical groups, Thrombotargets is currently focused on developing its own treatments,

       Biocat – 15 new therapies made in Catalonia                                                  8
and it has one of the most advanced therapies in development in the BioRegion of Catalonia,
TT-173, currently in phase III.

It is a topical, lyophilized antihemorrhagic agent which drastically lowers the bleeding time of
a surgical hemorrhage. TT-173 has already successfully passed a phase I clinical trial in
dental extraction and a phase II clinical trial in skin grafting, and it currently has a phase II/III
study underway in total knee arthroplasty, the results of which are expected in 2020.

Once the current phase II/III clinical trial is completed, the company will undertake a phase III
in liver surgery to complete the drug registration with the European Medicines Agency (EMA)
and the FDA in the United States.

Thrombotargets is headquartered in Castelldefels (Barcelona), where it conducts part of its
R&D. The company has new medical devices based on TT-173 in the preclinical phase. It is
currently in a capitalization phase for €12 million. Ever since it was created, Thrombotargets
has raised a total of €29 million from private investors and public domestic and European
funds.

       Biocat – 15 new therapies made in Catalonia                                                      9
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